2.1. Developmental and Neurogenic Stuttering.
Stuttering is a poorly understood condition marked by frequent repetitions or prolongations of sounds, and an impaired fluency of speech. Accessory features of stuttering, possibly resulting from the attempts of the stutterer to control the stuttering, include blocks in the flow of speech sounds, swallowing, grimacing, tremors of the jaw and tongue, coughing, rapid eye blinking, and jerking movements of the arm or upper trunk. (Brady, J. Am J Psychiatry, 1991, 148, 1309). One form, developmental stuttering, often appears in early human childhood or adolescence, and affects predominantly males. An estimated three million Americans are affected and the condition is not dependent on language type or cultural background. A less frequent type is neurogenic stuttering, often a result of head trauma or stroke. Subtle differences between neurogenic and developmental dysfluency may be observed, for example in the repetitive reading test, where sufferers of developmental stuttering often improve by the tenth reading of a passage, but sufferers of neurogenic stuttering do not. A third type is drug-induced stuttering, an increasingly frequent problem.
In the past, stutterers have been treated by a wide variety of methods devised by some of the best minds of the time. Both Hippocrates and Hieronymus Merculialis recommended oral or head surgeries or mutilations. In this century, psychiatric treatments have been tried ranging from operant reinforcement to psychotherapy for presumed unconscious conflicts. However, those who stutter are remarkably well-adjusted, and are similar to those who do not stutter in personality traits. Current methods include speech training and pharmaceutical intervention. The improvement for patients, unfortunately, has been limited.
The spectrum of experimental pharmaceutical interventions has been broad. At times, carbon dioxide inhalation, stimulants (notably methamphetamine), sedatives (in particular, phenobarbital combined with belladonna and ergotamine), an early antihistamine (hydroxyzinc), bromides, thiamine supplements, an antihypertensive (reserpine), the tranquilizer meprobamate, anxiolytics (in particular, benzodiazepines), neuroleptics (including thioridazine, chlorpromazine and trifluoperazine), verapamil, beta-adrenergic blockers (including propranolol, betaxolol, and oxprenolol), an anticonvulsant (carbamazepine), and cholinergic agents (neostigmine and bethanecol) have been tried for stuttering, but all with unsustainable success. Haloperidol has been particularly well studied as an agent for the attenuation of stuttering.
Notably Wells, P. G. et al. Br J Psychiatry 1971, 119, 603, reported a placebo-controlled, double-blind study. Wells et al., randomized patients into treatment groups, included objective measures of speech, and found a significant improvement over an eight-week course. Objective criteria in such studies include the length of time to read a standard passage, the number of syllabic repetitions in the process of conveying specific information, the time to explain a solution to a puzzle, and the like. Subsequent studies support a significant improvement in the accessory symptoms of stuttering, including rapid blinking and jerking movements of the upper body, but patient compliance is low because of side-effects including dizziness and dysphoric “medicine-head” symptoms. More significant and disturbing are the long-term detrimental effects haloperidol and other neuroleptics have on voluntary muscle function, known as tardive dyskinesia.
2.2 The GABAA Neuronal Pathway.
One of the main neurotransmitters involved in inhibitory neuronal pathways is gamma-aminobutyric acid or GABA. GABA appears to function mainly at two types of receptors, termed GABAA and GABAB receptors, that have different structures. The GABAA receptor is a GABA-gated chloride ion channel and the GABAB receptor is a G-protein coupled regulator of potassium conductance. GABA receptors can be modulated by several classes of pharmacologic agents, notably the benzodiazepines, the barbiturates, convulsants, and neurosteroids of the class epiallopregnanolone or epalons. These classes of agents appear to act at different, discrete sites on the GABAA receptor. Thus, the diversity of effects expressed by these agents ranges from the tranquilizing effects of benzodiazepines, and the sedative effects of barbiturates to the convulsant effects of t-butyl-bicyclophosphorothionate (TBPS), which may act on GABAA receptors associated with clathrin-coated vesicles. The cyclopyrrolones have demonstrated high affinity for the benzodiazepine binding site on the GABAA receptor. Some cyclopyrrolones, e.g., pagoclone, have a pharmacological profile consistent with that of a partial agonist at this site. Partial agonists can be efficacious in producing some effects, e.g., anxiolysis, in common with full agonists, but may be less effective in producing others, e.g., sedation. Antagonists, or “blockers,” on the other hand, counteract the action of endogenous GABA and exogenous agonists. Inverse agonists decrease the inherent or constitutive stimulation by a receptor in the absence of an agonist. Modulator is a term that includes agonist, partial agonist, inverse agonist, antagonist, neurotransmitter, reuptake inhibitor, and degradation inhibitor. Antagonists are often relatively specific to a particular class of agonists. For example, flumazenil, a benzodiazepine antagonist, blocks the function of benzodiazepines including flunitrazepam, diazepam, pinazepam, prazepam, halazepam, camazepam, and flurazepam.
GABAA receptor modulators, especially agonists and partial agonists, are also known to act as antiphobics, myorelaxants, anti-epileptics, and by other means. GABAA receptor modulators act as myorelaxants by decreasing muscle stiffness, decreasing tonus, and reducing voluntary muscle contraction in spasticity. Also some GABAA modulators have hypnotic, sleep-inducing, amnestic, sedative, and/or anti-convulsant effects. Antagonists of GABAA receptor function tend to block these effects and may even be anxiogenic or proconvulsant in some individuals.
Many of the GABAA agonists, in particular the benzodiazepines and the cyclopyrrolones, act to reduce anxiety and induce a sense of calm. In consequence, these agents are termed anxiolytics. It has long been thought that anxiety is a component of stuttering, although the cellular bases for anxiety and stuttering are not at all clear. In contrast, however, the results of placebo-controlled studies of benzodiazepines on stuttering have been inconsistent and disappointing (Brady, supra).
2.3 Drug-induced Stuttering.
A different approach, that of evaluating drug-induced stuttering, has led to some useful observations, but no cure. Part of the confusion is that many drugs induce stuttering. Several workers have reported that phenothiazines induce stuttering, whether administered alone or with other agents. This drug-induced stuttering was accompanied by akathisia, or a “can't sit still” syndrome. Rentschler, G. J. et al., J Fluency Disord 1984, 9, 265 and Elliot, R. I. et al., J Clin Psychopharmacol 1985, 5, 159, report stuttering in response to benzodiazepines. Alprazolam, a potent anxiolytic, can induce stuttering (Elliot, supra).
Most of the other cases of drug-induced stuttering are related to inhibition of serotonin uptake, usually with the drugs sertraline or fluoxetine (Brady, J. P. J Clin Psychopharmacol 1988, 18, 50), which are also considered to be anxiolytics. The induced stuttering was frequently accompanied by akathisia in these cases as well.
Thus, the state of the art underscores the prevailing and unfilled need for an effective pharmacologic treatment of stuttering. Indeed, the long-standing effort to cure or relieve stuttering has engaged many clinicians over decades, centuries, and even millennia. At least two conclusions may be reached from the wide range of pharmacologic treatments attempted for stuttering. The first is that no clear understanding of the underlying basis for stuttering exists. The study of stuttering is particularly intractable because there exist no animal models and the evaluation of improvement in stuttering is fraught with subjective criteria. The second is that no known agent, or combination of agents, is effective in treating this widespread difficulty.